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Atomic Details of the Interactions of Glycosaminoglycans with Amyloid-β Fibrils
- Stewart, Katie
L., Hughes, Eleri, Yates, Edwin A., Akien, Geoffrey R., Huang, Teng-Yi, Lima, Marcelo A., Rudd, Timothy R., Guerrini, Marco, Hung, Shang-Cheng, Radford, Sheena E., Middleton, David A.
- Journal of the American Chemical Society 2016 v.138 no.27 pp. 8328-8331
- Alzheimer disease, amyloid, carbon, heparin, histidine, isotope labeling, models, nuclear magnetic resonance spectroscopy, peptides, stable isotopes
- The amyloid plaques associated with Alzheimer’s disease (AD) comprise fibrillar amyloid-β (Aβ) peptides as well as non-protein factors including glycosaminoglycan (GAG) polysaccharides. GAGs affect the kinetics and pathway of Aβ self-assembly and can impede fibril clearance; thus, they may be accessory molecules in AD. Here we report the first high-resolution details of GAG–Aβ fibril interactions from the perspective of the saccharide. Binding analysis indicated that the GAG proxy heparin has a remarkably high affinity for Aβ fibrils with 3-fold cross-sectional symmetry (3Q). Chemical synthesis of a uniformly ¹³C-labeled octasaccharide heparin analogue enabled magic-angle spinning solid-state NMR of the GAG bound to 3Q fibrils, and measurements of dynamics revealed a tight complex in which all saccharide residues are restrained without undergoing substantial conformational changes. Intramolecular ¹³C–¹⁵N dipolar dephasing is consistent with close (<5 Å) contact between GAG anomeric position(s) and one or more histidine residues in the fibrils. These data provide a detailed model for the interaction between 3Q-seeded Aβ40 fibrils and a major non-protein component of AD plaques, and they reveal that GAG–amyloid interactions display a range of affinities that critically depend on the precise details of the fibril architecture.